BCS classification of drugs.pdf

FOR YOU

1. Working document QAS/04.109/Rev.1
page 1

WORLD HEALTH ORGANIZATION
ORGANISATION MONDIALE DE LA SANTE



PROPOSAL TO WAIVE IN VIVO BIOEQUIVALENCE REQUIREMENTS
FOR THE WHO MODEL LIST OF ESSENTIAL MEDICINES
IMMEDIATE RELEASE, SOLI D ORAL DOSAGE FORMS


© World Health Organization 2005
All rights reserved.
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft.
The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part
or in whole, in any form or by any means outside these individuals and organizations (including the organizations’
concerned staff and member organizations) without the permission of WHO. The draft should
not be displayed on any website.
Please send any request for permission to:
Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards
(PSM), World Health Organization, CH-1211 Geneva 27, Switzerland.
Fax: [phone]; e-mails: [email protected]; [email protected]
The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or
area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent
approximate border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
The World Health Organization does not warrant that the information contained in this draft is complete and
correct and shall not be liable for any damages incurred as a result of its use.
This document has been revised by Professor Jennifer B. Dressman, Institut für
Pharmazeutische Technologie, Biozentrum, Johann Wolfgang Goethe-Universität,
Frankfurt/Main, Germany. It has followed the steps given in the schedule on page 2 herein.
It has been very widely distributed and numerous comments have been incorporated.
Please address any comments and/or corrections you may have to Dr S. Kopp, Quality
Assurance and Safety: Medicines, Medicines Policy and Standards,
World Health Organization, 1211 Geneva 27, Switzerland, fax: [phone]
or e-mail: [email protected] (with a copy to [email protected]) by 20 October 2005.

2. Working document QAS/04.109/Rev.1
page 2






SCHEDULE
FOR THE ADOPTION PROCESS OF DOCUMENT QAS/04.109/REV.1:
Proposal to waive in vivo bioequivalence requirements for the WHO
Model List of Essential Medicines
immediate release, solid oral dosage forms




Deadline
Consolidation of first list for consideration of biowaiver October 2004
Consolidation of comments March 2005
Discussion during consultation July 2005
Additional studies and review

August-September 2005
Mailing of revised version for comments September 2005
Presentation to Fortieth WHO Expert Committee on
Specifications for Pharmaceutical Preparations
24-28 October 2005

3. Working document QAS/04.109/Rev.1
page 3




Proposal to waive in vivo bioequivalence requirements for
WHO Model List of Essential Medicines
immediate release, solid oral dosage forms




ABBREVIATIONS USED

API Active Pharmaceutical Ingredient

BE Bioequivalence

BCS Classification System

Biowaiver Approval of a generic oral solid formulation of an API based on strictly
defined dissolution criteria as a surrogate for an in vivo bioequivalence test
(provided other aspects of the dossier are deemed acceptable according to
the usual criteria).

EML WHO Model List of Essential Medicines

HHS-FDA Department of Human Health: Fede ral Drug Agency, the United States of
America

Multisource document
WHO working document QAS/04.093 entitled "Revision of multi-source
(generic) pharmaceutical products: guidelines on registration requirements
to establish interchangeability"

SUPAC Scale-up and post-approval changes



INTRODUCTION

This proposal is closely linked to the working document QAS/04.093/Rev.4, entitled Revision of
multi-source (generic) pharmaceutical products: guidelines on registration requirements to
establish interchangeability ("Multisource document"). It aims to give national authorities
sufficient background information on the various orally applied APIs on the WHO Model List of
Essential Medicines (EML) to enable them to make an informed decision, also taking into account

4. Working document QAS/04.109/Rev.1
page 4


local usage of the API, as to whether generic formulations should be subjected to in vivo
bioequivalence (BE) studies or whether a Biowaiver can be applied. In light of scientific work and
discussion in the last decade, some of the criteria used to evaluate the API in terms of potential for
a Biowaiver have been revised to allow a broadened scope of application. The result is that many
APIs on the EML can now be considered for the Biowaiver procedure, subject to the usage and
risks in the national setting.

BACKGROUND: HHS-FDA INITIATIVE S TO ALLOW BIOWAIVERS BASED
ON THE BCS

In 1995 the American HHS-FDA instigated the Biopharmaceutics Classification System
(BCS), with the aim of granting so-called Biowaivers for SUPAC changes
(www.fda.gov/cder/guidance/cmc5.pdf). A Biowaiver means that in vivo bioavailability
and/or bioequivalence studies may be waived (not considered necessary for product
approval). Instead of conducting expensive and time consuming in vivo studies, a
dissolution test could be adopted as the surrogate basis for the decision as to whether the
two pharmaceutical products are equivalent. At that time the Biowaiver was only
considered for scale-up and post approval changes (SUPAC) to pharmaceutical products.

More recently, the application of the Biowaiver concept has been extended to approval of
certain orally administered generic products (www.fda.gov/cder/guidance/3618fnl.htm).

Within the context of the documents cited above, only APIs with high solubility and high
permeability and which are formulated in solid, immediate release (IR) oral formulations
can be approved on the basis of the Biowaiver procedure. A major advantage of the
Biowaiver procedure is the simplification and reduction of time required for product
approval, thus reducing the cost of bringing new products to market.

What is the BCS?
The Biopharmaceutics Classification System or BCS was proposed in 1995 by Amidon et
al. (Pharm. Res. 1995 March; 12(3):413-20). It is a scientific framework which divides
APIs into four groups, according to their solubility and permeability properties.

Classification of APIs according to the BCS
According to the HHS-FDA definitions in the documents cited above, the four different
categories possible for an API according to the BCS are:

• BCS class I: “high” solubility – “high” permeability
• BCS class II: “low” solubility” – “high” permeability
• BCS class III: “high” solubility – “low” permeability
• BCS class IV: “low” solubility – “low” permeability

5. Working document QAS/04.109/Rev.1
page 5
Depending on the classification, the oral availability of the API may be expected to range
from heavily dependent on the formulation and manufacturing method (e.g. class 2 APIs:
poorly soluble yet highly permeable) to mostly dependent on the API permeability
properties (e.g. Class III APIs: highly soluble yet poorly permeable).

How is high or low solubility currently defined by HHS-FDA?
The aqueous solubility of a drug substance is considered as high according to the HHS-
FDA BCS criteria when:

- The ratio of the highest orally administered dose (in mg) to the solubility (mg/ml)
is less than 250 ml

- This criterion is met over the pH range 1-7.5 at 37°C

According HHS-FDA guidances, the determination of the equilibrium solubility should
be carried out with the shake-flask method (other methods like acid or base titration are
permitted, when their ability to predict the equilibrium solubility is justified). The
experiments should be carried out a temperature of 37+
1°C. Further, a sufficient number
of pH conditions should be chosen to cover the pH range of 1-7.5 and each determination
should be carried out at least in triplicate. The buffer solutions given in the USP are
appropriate for the tests, but other buffers are also allowed for the experiments. The pH
value of each buffer solution should be checked before and after each experiment.
Degradation of the API due to pH or buffer composition should also be reported along
with other stability data.

The reason for the 250 ml cut-off criterion for the dose:solubility ratio is that in
pharmacokinetic bioequivalence studies, the API formulation is to be ingested with a
large glass of water (8 ounces corresponds to about 250 ml). If the highest orally
administered dose can be completely dissolved in this amount of water, independent of
the physiological pH value (hence the determination over the pH range 1-7.5), solubility
problems are not expected to hinder the uptake of the drug in the small intestine.

The other important parameter for the BCS is the intestinal permeability of the drug.

How is high or low permeability currently defined by HHS-FDA ?
According to HHS-FDA a drug is considered a highly permeable, when more than 90%
of the orally administered dose is absorbed in the small intestine.

Permeability can be assessed by pharmacokinetic studies (mass balance studies for
example), or intestinal permeability methods, e.g. intestinal perfusion in humans, animal
models or Caco 2 cell lines or other suitable, validated cell lines. In vivo or in situ animal
models or in vitro models (cell lines) are only considered appropriate by HHS-FDA for
passively transported drugs. It should be noted that all of these measurements assess the
faction absorbed (as opposed to the bioavailability, which can be reduced substantially by
first pass metabolism).

6. Working document QAS/04.109/Rev.1
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HHS-FDA suggests use of two different methods if results with one method are
inconclusive for the permeability classification.

Which pharmaceutical formulations can currently be considered for a biowaiver
according to HHS-FDA?
In order to be considered bioequivalent according to the HHS-FDA Biowaiver procedure,
a pharmaceutical product:

• should contain a class 1 substance

• should be rapidly dissolving, meaning it should release at least 85% of its content
in 30 minutes in three different buffers (pH 1.2, pH 4.5 and pH 6.8, composition
see multi source document) in a paddle (50 rpm) or basket (100 rpm) apparatus at
37°C and a volume of 900 ml

• should not contain excipients which could influence the absorption of the drug

• should not contain a drug with a narrow therapeutic index

• should not be designed to be absorbed from the oral cavity.

The reasoning for the above-mentioned dissolution restriction is that when a highly
soluble, highly permeable drug dissolves rapidly, it behaves like a solution in the
gastrointestinal tract. If this is the case, the pharmaceutical composition of the product is
insignificant, provided that excipients which influence the uptake across the gut wall are
excluded from the formulation. The API is not prone to precipitation after its dissolution
due to its good solubility under all pH conditions likely to be found in the upper
gastrointestinal tract. The high permeability assures the complete uptake (> 90%) of the
API during its passage through the small intestine. The fast dissolution of the product
guarantees that the API is available long enough for the uptake in small intestine (the
passage time in the small intestine is approximately 4 hours) and negates any slight
differences between the formulations.

Pharmaceutical products containing an API with a narrow therapeutic index should
always be tested with in vivo methods, since the risk for the patient resulting from a
possible incorrect bioequivalence decision using the Biowaiver procedure is considered
too high with these kinds of APIs.

As the BCS is only applicable to drugs which are absorbed from the small intestine, drugs
with different sites of absorption (oral cavity) are not eligible for a Biowaiver.

It can be easily seen that the HHS-FDA requirements for classification of APIs and
eligibility criteria for the Biowaiver are very strict. In the last decade, several publications
and continuing scientific discussions have suggested that the original HHS-FDA criteria
for application of the Biowaiver procedure can be relaxed without substantially

7. Working document QAS/04.109/Rev.1
page 7
increasing the risk to public health or to the individual patient. On the basis of these
publications and dialogue, the WHO has proposed revised BCS criteria and additional
considerations for the eligibility of a pharmaceutical product for the Biowaiver procedure
in the Multisource document.

WHO REVISIONS TO THE CRITE RIA FOR BCS CLASSIFICATION

Based upon numerous discussions and consultations, the WHO revisions to the BCS
criteria are as newly suggested in the working document QAS/04.093, Rev. 4, entitled
Revision of multi-source (generic) pharmaceutical products: guidelines on registration
requirements to establish interchangeability ("Multisource document") as follows:

WHO high solubility definition

When an API shows a dose/solubility ratio of less than 250 ml at 37°C over a pH
range of 1.2-6.8, it can be classified as “highly soluble”. The decrease in pH from
7.5 in the FDA Guidances to 6.8 reflects the need to dissolve the drug before mid-
jejunum to ensure enough reserve length for absorption from the GI tract.
Furthermore, the dose that is to be used for the calculation is the highest dose
indicated in the Model List, even though in some countries other doses may be
available on the market.

WHO permeability definition

When an API is absorbed to an extent of 85% or more, it is considered to be
“highly permeable”. The permeability criterion was relaxed from 90% in the FDA
Guidances to 85% in the WHO multisource document. Some examples of APIs
now included in BCS class I that were previously considered to be Class III are:
paracetamol, acetylsalicylic acid, allopurinol, lamivudine, promethazine.

Application of these revised criteria has changed the classification of some APIs in the list. Thus,
the classifications in the tables attached to this document supercede those in previous publications.
As new APIs on the Model List, it will be necessary to classify these according to the revised
BCS, so it is anticipated that the Tables will be revised regularily. In addition, some APIs have not
yet been sufficiently characterized to assign a BCS classification. As the Tables evolve, it is
anticipated that more concrete information will be generated for these APIs as well.

The potential impact of the revised guidelines on registration requirements to establish
interchangeability is that a large number of medicines on the EML could become eligible for
approval based on in vitro bioequivalence testing in accordance with the dissolution tests
prescribed in Section 9 of the Multisource document.

WHO EXTENSIONS TO THE SCOPE OF APPLICATION OF THE BIOWAIVER

In the "Multisource document" WHO has broadened the scope of application of the
Biowaiver in three directions:

8. Working document QAS/04.109/Rev.1
page 8


1) The criteria for classification as a Class I API have been relaxed with respect
to both the dose: solubility ratio and permeability requirements.

2) The new version of the document allows pharmaceutical products containing
Class III APIs to be considered for a Biowaiver, with application of more
stringent dissolution criteria.

3) The new version of the document further allows pharmaceutical products
containing BCS class II APIs that are weak acids which can meet a
dose:solubility ratio of 250 ml or less at pH 6.8 to be eligible for a Biowaiver,
with the requirement that they dissolve rapidly at pH 6.8 and similarly to the
comparator product at pH 1.2 and 4.5.

WHO ADDITIONAL CRITERIA FOR AP PLICATION OF THE BIOWAIVER
PROCEDURE

For all APIs on the EML, it is imperative to consider not only the physical and absorption
properties of the API when evaluating the API for Biowaiver, but (as outlined in the
Multisource document) to perform a benefit/risk analysis in view of usage at the national
level. As an example, in some countries amoxicillin is used primarily for ambulatory
patients with mild to moderate upper respiratory tract, urinary tract and other infections.
In other countries, amoxicillin might also be used for severe or even life-threatening
infections, in which case the risk to the patient of arriving at the wrong bioequivalence
decision would be far greater.

Thus, the eligibility criteria according to WHO are

1. The BCS classification (according to the revised criteria) of the API.

2. Risk assessment: Only if the risk of an incorrect biowaiver decision and an
evaluation of the consequences (of an incorrect, Biowaiver-based equivalence
decision) in terms of public health and individual patient risks outweighed by the
potential benefits of the Biowaiver approach should the Biowaiver procedure be
applied.

3. Dissolution requirements for the pharmaceutical product:
- Very rapidly dissolving (release of >85% of the labelled amount of drug in
15 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rotational speed
of 75 rpm in the paddle apparatus or 100 rpm in the basket apparatus
(applies to pharmaceutical products containing Class III APIs).

- Rapidly dissolving (release of >85% of the labelled amount of drug in 30
minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rotational speed of
75 rpm in the paddle apparatus or 100 rpm in the basket apparatus (applies
to pharmaceutical products containing Class I APIs and Class II APIs

9. Working document QAS/04.109/Rev.1
page 9
which are weak acids and meet the 250 ml dose:solubility requirement at
pH 6.8).

4. Excipient considerations
The national authority should be mindful that some excipients can influence
motility and/or permeability in the gastrointestinal tract. Therefore, the excipients
used in the multisource product formulation should be scrutinized. In this regard,
the national authority can draw on the experience of formulations which have
been approved on the basis of human bioequivalence studies in their own or in
other jurisdictions.

If the multisource product under consideration contains excipients that have been
used before in similar amounts in other formulations of the same API, it can be
reasonably concluded that the excipients will have no unexpected influence on the
bioavailability of the product. If, however, the formulation contains different
excipients or very different amounts of the same excipients, the national authority
may choose not to allow the Biowaiver procedure to be used.

A list of usual and acceptable excipients can be found e.g. at the following
website: (www.fda.gov/cder/iig/iigfaqWEB.htm), formulations of some products
can be found on national websites of national drug regulatory authorities.

Explanation of the Tables
The decision of a national authority to allow a biowaiver based on the BCS should take
into consideration the solubility and permeability characteristics as well as the therapeutic
use and therapeutic index of the active pharmaceutical ingredient (API), its pharmaco-
kinetic properties, the similarity of the dissolution profiles of the multisource and the
comparator products in standard buffers with a pH of 1.2, pH 4.5 and pH 6.8 at 37°C.
Data related to the excipient composition of the multisource product is also required. A
systematic approach to the biowaiver decision has been established by the International
Pharmaceutical Federation (FIP) and published in the Journal of Pharmaceutical
Sciences:
http://www3.interscience.wiley.com/cgi-bin/jhome/68503813
. They can further be
downloaded from the International Pharmaceutical Federation (FIP) website:
http://www.fip.org/
. These monographs provide detailed information which should be taken
into account whenever available in the Biowaiver consideration.

Which APIs are included in the Tables?
The substances listed on the 14
th
EML as of March 2005 have been evaluated and
classified according to the revised criteria given above.

Where do the data come from?
The solubility and permeability values were found in the literature open to the public
domain, such as the Martindale, the Merck Index, scientific journals, etc.

10. Working document QAS/04.109/Rev.1
page 10


Please note that the doses used for the calculation of the dose/solubility ratio are the doses
given in the EML.

The indications given in the Tables are taken directly from the EML. If the EML
specifies the dosage form (e.g. sublingual tablet) this is indicated under “comments”.

“Worst case” approach to BCS classification
The drugs listed in the EML were classified according to the criteria explained above.
Where no clear classification could be made, the “worst case” was assumed, for example
if a substance is highly soluble but absolute bioavailability data were not available, the
test for BCS class III substances has been proposed. The same procedure was adopted for
fixed combinations, for example amoxicillin and clavulanic acid, the testing procedure
was always fixed according to the “worst” BCS classification, in this example clavulanic
acid (BCS class 3/1), since amoxicillin is a BCS class I drug. So this combination would
be tested according to BCS class III requirements.

The results of the revised classification can be found in Tables A – C.

Why are there three Tables?
In Table A, all APIs on the EML that are applied orally are listed, with the exception of
the APIs listed as complementary. In Table B, the APIs listed as complementary in the
EML are summarized and in Table C, APIs for which there had previously been no
classification or had been introduced with the 14
th
edition version of the EML
(March 2005) are listed, along with a more detailed explanation of their classification.

Risk assessment
In order to minimize the risks of an incorrect biowaiver decision in terms of public health
and individual patient risks the therapeutic indications of the API, known
pharmacokinetic variations, food effects, etc should be evaluated based on local clinical
experience, taking into account the indications for which the API is prescribed in that
country as well as specific pharmacokinetic population variations (for example CYP
polymorphisms). Known potential risks are listed under “potential risks” in the Tables.
The absence of an entry under “potential risks” should not however be misconstrued as
meaning that there are no risks associated with the use of the medicine.

BIOWAIVER TESTING PROCEDURE ACCORDING TO WHO

Depending on the BCS classification of the API, based on solubility and permeability
characteristics listed in the accompanying Tables, the testing procedure is defined in 9.2.1
of the "Multisource document".

11. Working document QAS/04.109/Rev.1
page 11
For pharmaceutical products containing BCS class I (highly soluble, highly permeable)
APIs:
For rapidly dissolving (as defined above) pharmaceutical products containing BCS class
I APIs, greater than 85% dissolution of the labelled amount is required within 30min in
standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75rpm or alternatively
the basket apparatus at 100rpm. The dissolution profiles of the comparator and the
multisource products should be compared by an f
2 > 50 or an equivalent statistical
criterion.

If after 15 min more than 85% are released from the comparator and the multisource
formulation under the above-mentioned conditions the product will be considered very
rapidly dissolving. In this case the products are deemed to be equivalent and a profile
comparison is not required.

For pharmaceutical products containing BCS class III (highly soluble, low permeability
)
APIs:
A biowaiver can be only considered if both the multisource and the comparator product
are very rapidly dissolving; 85% or more dissolution of the labelled amount of the API
should be achieved within 15min in standard media at pH 1.2, 4.5 and 6.8 using the
paddle apparatus at 75rpm or alternatively the basket apparatus at 100 rpm.

Generally the risks of an inappropriate biowaiver decision should be more critically
reviewed (side specific absorption, induction/competition at the absorption side, excipient
composition and therapeutic risks, etc.) than for BCS class I drugs.

For pharmaceutical products containing APIs with high solubility at pH 6.8 but not at pH 1.2 or
4.5 and with high permeability (by definition, BCS class II compounds with weak acidic
properties):
These are eligible for a Biowaiver provided that the multisource product:

(i) is rapidly dissolving i.e. 85% or more dissolution of the labelled amount of the API
should be achieved within 30 min in standard media at pH 6.8 using the paddle
apparatus at 75 rpm or alternatively the basket apparatus at 100rpm, and


(ii) The multisource product exhibits similar dissolution profiles, as determined with the
f
2 value or equivalent statistical evaluation, to those of the comparator product in
buffers at all three pH values (pH 1.2, 4.5 and 6.8).

For multisource products containing Class 2 APIs with dose:solubility ratios of 250 ml or less at
pH 6.8, the excipients should additionally be critically evaluated in terms of type and amounts of
surfactants in the formulation.

Further details about eligibility for the Biowaiver and appropriate test procedures can be found in
Section 5 and 9 of the Multisource document.

12. Working document QAS/04.109/Rev.1
page 12

Table A. Substances on the WHO Essential Medicines List (EML)

Drug
a

Highest oral
strength
according to
WHO Essential
Medicines List
a
Solubility
b
Permeability
c

BCS
class
d

Dissolution test
(for biowaiver)
e
Potential risks
f
Indication(s)
according to WHO
Essential Medicines
List (EML)
g

Comments
and special
dosage form
indications
a

abacavir 200mg high low 3 9.2.1.2 antiretroviral acetazolamide 250mg low low 4 no biowaiver
antiglaucoma
medicine
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
acetylsalicylic acid 500mg high high 1 9.2.1.1
NSAID, antimigraine
medicine acetylsalicylic acid 100mg high high 1 9.2.1.1
antithrombotic
medicine aciclovir 200mg high low 3 9.2.1.2 antiherpes medicines albendazole 400mg low low 4 no biowaiver anthelminic
chewable tablet;
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
allopurinol 100mg high high 1 9.2.1.1 gout aluminium hydroxide
500mg


N.R.
N.A.

antacid
local effect
amiloride hydrochloride 5mg high high 1 9.2.1.1 diuretic amitriptyline hydrochloride 25mg
1
high high 1 9.2.1.1
psychotherapeutic
medicine
amlodipine
5mg
high
high
1
9.2.1.1

antihypertensive medicine

13. Working document QAS/04.109/Rev.1
page 13

amodiaquine (base)
200mg
high
borderline BA > 75%
3/1
9.2.1.2
CYP2C8 polymorphism, increased risk for agranulocytosis and liver toxicity
antimalarial
extent of first pass metabolism uncertain
amoxicillin (a) + clavulanic acid (c)
(a) 500mg + (c) 125mg
(a) high + (c) high
(a) high + (c) borderline absorption > 73% (radioactive excretion)
(a) 1 + (c) 3/1
9.2.1.2

antibacterial
combination should be tested according to clavulanic acid requirements
amoxicillin anhydrous 500mg high high 1 9.2.1.1 antibacterial artemether (a) +
lumefantrine (l)
(a) 20mg +
(l) 120mg
(a and l)
unknown low (a and l)
(a) 4/3
+ (l) 4/3no biowaiver antimalarial
ascorbic acid 50mg high high 1 9.2.1.1 vitamin atenolol 100mg high low 3 9.2.1.2
antianginal,
antihypertensive,
antiarrhythmic,
medicine and used
in heart failure
azithromycin
500mg
low
low
4
no biowaiver

antibacterial
unknown whether poor BA is due to poor solubility or poor solubility and permeability
benznidazole 100mg high low 3 9.2.1.2
american
tripanosomiasis biperiden hydrochloride 2mg high
insufficient
literature 3/1 9.2.1.2
antiparkinson
medicine

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carbamazepine 200mg low (neutral) high 2 no biowaiver
antiepileptic,
psychotherapeutic
medicine scored tablet
cefixime
400mg
low
low
4
no biowaiver

antibacterial
unknown whether poor BA is due to poor solubility or poor solubility and permeability
chloramphenicol 250mg high low 3 9.2.1.2
narrow therapeutic
index antibacterial chloroquine phosphate or sulfate 150mg high high 1 9.2.1.1 DMARD, antimalarial chlorphenamine
hydrogen maleate 4mg high
BA 25-59%, first
pass 3/1 9.2.1.2
CYP2D6
polymorphism antiallergic
extent of first
pass metabolism
uncertain
chlorpromazine hydrochloride 100mg high low 3 9.2.1.2
psychotherapeutic
medicine ciprofloxacin
hydrochloride 250mg high
low/high, BA 70-
82%, possible
first pass, high in
CaCo 2 cells 3/1 9.2.1.2 antibacterial
extent of first
pass metabolism
uncertain
clofazimine 100mg
insufficient
literature low 4/3
no biowaiver
at present antileprosy medicine clomifene citrate 50mg high
insufficient
literature 3/1 9.2.1.2 ovulation inducer

15. Working document QAS/04.109/Rev.1
page 15
clomipramine
hydrochloride 25mg high



Some 66% of a
dose is excreted
in the urine, the
remainder being
eliminated in the
faeces 3/1 9.2.1.2
psychotherapeutic
medicine
lack of absolute
bioavailability data
cloxacillin (as sodium salt) 1000mg high low 3 9.2.1.2 antibacterial codeine phosphate 30mg high low 3 9.2.1.2 risk of abuse
opionid analgesic,
diarrhoea in adults dapsone 100mg
low (weak
base) high 2 no biowaiver G6PD defiency antileprosy medicine diazepam 5mg high high 1 9.2.1.1
psychotherapeutic
medicine scored tablet didanosine 200mg high low 3 9.2.1.2 antiretroviral
buffered chewable,
dispersible tablet didanosine 400mg high low 3 9.2.1.2 antiretroviral
unbuffered enteric
coated capsule digoxin 250µg high high 1 9.2.1.1
antiarrhythmic and
used in heart failure diloxanide furoate 500mg low
2
low 4 no biowaiver antiprotozoal
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
DL-methionine 250mg high high 1 9.2.1.1 antidote doxycycline hydrochloride 100mg high high 1 9.2.1.1 antibacterial

16. Working document QAS/04.109/Rev.1
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efavirenz 200mg low
1
low 4 no biowaiver antiretroviral
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
enalapril
2,5mg
high
low
3
9.2.1.2

antihypertensive medicine

ergocalciferol
1.25mg (50 000
IU) high low 3 9.2.1.2 vitamin erythromycin stearate +
succinate 250mg high low 3 9.2.1.2 antibacterial
ethambutol
hydrochloride 400mg high low 3 9.2.1.2
risk of dose
related
ototoxicity antituberculosis medicine
ethinylestradiol 50µg high
borderline, BA 40-
50%, first pass 3/1 9.2.1.2 estrogen
extent of first pass
metabolism
uncertain ethinylestradiol (e) + levonorgestrel (l) 30µg + 150µg high
(e) borderline, BA
40-50%, first pass
+ (l) high 3/1 + 1 9.2.1.2 hormonal contraceptive
extent of first pass
metabolism
uncertain;
combination should
be tested according to
ethinylestradiol
requirements
ethinylestradiol (e) + norethisterone (n) 35µg + 1mg high
(e) borderline, BA
40-50%, first pass
+ (n) high 3/1 + 1 9.2.1.2 hormonal contraceptive
extent of first pass
metabolism uncertain;
combination should
be tested according to
ethinylestradiol
requirements

17. Working document QAS/04.109/Rev.1
page 17

ferrous salt
equivalalent to 60mg iron
high (see footnote)
low
3
9.2.1.2

antianaemia medicine
commonly used salts: see footnote
ferrous salt (fs) + folic acid (fa)
equivalent to 60mg iron + 400µg folic acid
(fs) high + (fa) high
(fs) low + (fa) low (urinary recovery 28.5%
2
)
3 + 3/1
9.2.1.2

antianaemia medicine (during pregnancy)
lack of absolute bioavailability data; commonly used salts: see footnote; combination should be tested according to ferrous salt requirements
fluconazole 50mg high high 1 9.2.1.1 antifungal folic acid
5mg
high
low
3/1
9.2.1.2

antianaemia medicine
lack of absolute bioavailability data
furosemide 40mg low low 4 no biowaiver highly variable BA
medicine used in heart
failure, diuretic
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
glibenclamide 5mg low low 4 no biowaiver antidiabetic agent
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
glyceryl trinitrate
500µg
high
sublingual application, permeability in the oral cavity more important than GI permeability
3/1
N.A.
local absorption
antianginal medicine
sublingual application

18. Working document QAS/04.109/Rev.1
page 18



griseofulvin 250mg low (neutral) high 2 no biowaiver antifungal
haloperidol 2mg
borderline, <
0.01 mg/ml
2
low 4/3 no biowaiver psychotherapeutic medicine
hydralazine
hydrochloride 50mg high low 3 9.2.1.2 antihypertensive medicine
hydrochlorothiazide 25mg high low 3 9.2.1.2
antihypertensive medicine,
diuretic and used in heart failure scored tablet ibuprofen 400mg
low, weak acid
[pK
a
4.4, 5.2] high 2 9.2.1.3 NSAID, antimigraine medicine
indinavir sulfate 400mg low low 4 no biowaiver
CYP 450 3A4,
food effect (-) antiretroviral
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
iopanoic acid 500mg
low, weak acid,
[pk
a
4.8]
2

(see footnote)


high 2 no biowaiver radiocontrast media
isoniazid 300mg high borderline 3/1 9.2.1.2 antituberculosis medicine isoniazid (i) + ethambutol (e)
(i) 150mg + (e) 400mg
(i) high + (e) high
(i) borderline + (e) low
(i) 3/1 + (e) 3
9.2.1.2

antituberculosis medicine

isosorbide dinitrate
5mg
high
sublingual application, permeability in the oral cavity more important than GI permeability
3/1
N.A.

antianginal medicine
sublingual

19. Working document QAS/04.109/Rev.1
page 19

ivermectin 6mg
insufficient
literature,
practically
insoluble in
wate
r
3

D/L>6000ml low 4/3 no biowaiver antifilarial
scored tablet;
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
lamivudine 150mg high high 1 9.2.1.1 antiretroviral levamisole hydrochloride 150mg high borderline 3/1 9.2.1.2 anthelminic levodopa (l) + carbidopa (c)
(l) 250mg + (c) 25mg
(l) high + (c) high
(l) high + (c) insufficient data (BA
humans

58%, BA
dogs
88%)
(l) 1 + (c) 3/1
9.2.1.2
narrow therapeutic index
antiparkinson medicine
extent of human first pass metabolism uncertain; combination should be tested according to carbidopa requirements
levonorgestrel 30µg high high 1 9.2.1.1 hormonal contraceptive levonorgestrel
750µg * 2 (pack of
two) high high 1 9.2.1.1 hormonal contraceptive levothyroxine sodium salt 100µg high low 3 9.2.1.2
narrow
therapeutic index thyroid hormone lithium carbonate 300mg high high 1 9.2.1.1
narrow
therapeutic index
psychotherapeutic
medicine lopinavir (l) + ritonavir (r)
(l) 133.3mg +
(r) 33.3mg
(l) low +
(r) low
(l) low (insufficient
data) +
(r) low
(l) 4/2 +
(r) 4 no biowaiver antiretroviral
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
mebendazole
500mg
low
low
4
N.A.

anthelminic
chewable tablet; anthelmintics usually applied orally for action in GI tract: solubility more important

20. Working document QAS/04.109/Rev.1
page 20


than permeability - but unknown whether poor BA is due to poor solubility or poor solubility and permeability

21. Working document QAS/04.109/Rev.1
page 21

mefloquine hydrochloride 250mg low
2
low 4 no biowaiver antimalarial
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
metformin hydrochloride 500mg high low 3 9.2.1.2 antidiabetic agent methyldopa 250mg high low 3 9.2.1.2 antihypertensive medicine metoclopramide
hydrochloride 10mg high low 3 9.2.1.2 antiemetic
metronidazole 500mg high high 1 9.2.1.1 antiprotozoal, antibacterial morphine sulfate 10mg high
insufficient data (BA ~
30% but extensive
first pass) 3/1 9.2.1.2 risk of abuse opionid analgesic
extent of first pas
s
metabolism
uncertain
nelfinavir mesilate 250mg low low 4 no biowaiver
CYP 450 3A4, food
effect (+) antiretroviral
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
neostigmine bromide 15mg high low 3 9.2.1.2 muscle relaxant nevirapine 200mg
low (weak
base) high 2 no biowaiver antiretroviral niclosamide
500mg
low
low
4
N.A.

anthelminic
chewable tablet; anthelmintics usually applied orally for action in GI tract: solubility more important than permeability
nicotinamide 50mg high high 1 9.2.1.1 vitamin nifedipine 10mg
low, weak
acid, solubility
at pH 7
0.0056
mg/ml
2
high 2 no biowaiver antioxytocic

22. Working document QAS/04.109/Rev.1
page 22



nifurtimox 250mg high low 3 9.2.1.2
american
tripanosomiasis
nitrofurantoin 100mg
low, weak
acid, solubility
at pH 7.0
0.374 mg/ml
[pK
a
7.2 (25°)]
2
high 2 no biowaiver antibacterial
norethisterone 5mg high high 1 9.2.1.1 progestogen nystatin
500 000 IU


N.R.
N.A.

antifungal
local effect
paracetamol 500mg high high 1 9.2.1.1
NSAID, antimigraine
medicine penicillamine 250mg high low 3 9.2.1.2 antidote phenobarbital 100mg high high 1 9.2.1.1
narrow therapeutic
index antiepileptic phenoxymethylpenicillin
(as potassium salt) 250mg high high 1 9.2.1.1 antibacterial
phenytoin sodium salt 100mg
low, weak
acid, sol. at
pH 6.8 1.7
mg/ml
4
[pK
a
8.3 (25°)]) high 2 9.2.1.3
narrow therapeutic
index, non-linear
pharmacokinetics antiepileptic
potassium iodide
60mg
high
high
1
9.2.1.1

thyroid hormones and antithyroid medicines

praziquantel 600mg low (neutral) high 2 no biowaiver
anthelminic,
antischistosomal,
antitrematode prednisolone 25mg high high 1 9.2.1.1 antiallergic primaquine diphosphate 15mg high high 1 9.2.1.1 antimalarial proguanil hydrochloride 100mg high high 1 9.2.1.1 antimalarial promethazine
hydrochloride 25mg high high 1 9.2.1.1 CYP2D6 polymorphism antiemetic
propranolol
hydrochloride 40mg high high 1 9.2.1.1 antimigraine medicine

23. Working document QAS/04.109/Rev.1
page 23
propylthiouracil 50mg high high 1 9.2.1.1 antithyroid medicine
pyrantel embonate
250mg
low
low
4
N.A.

anthelminic
chewable tablet; anthelmintics usually applied orally for action in GI tract: solubility more important than permeability

24. Working document QAS/04.109/Rev.1
page 24



pyrazinamide 400mg high borderline 3/1 9.2.1.2
antituberculosis
medicine
pyridoxine hydrochloride 25mg high high 1 9.2.1.1 vitamin pyrimethamine 25mg
borderline;
<0.1 mg/ml
3
low 4/3 no biowaiver
antipneumocystosis and
antitoxoplasmosis
medicine
quinine bisulfate or sulfate 300mg high high 1 9.2.1.1 antimalarial ranitidine hydrochloride
150mg
high
low
3
9.2.1.2

antiulcer medicine

retinol palmitate
110mg (200 000
IU) low
3
low 4 no biowaiver vitamin
unknown whether
poor BA is due to
poor solubility or poor
solubility and
permeability
riboflavin 5mg high high 1 9.2.1.1 vitamin rifampicin 300mg
low
(amphiphil)
[pK
a
1.7, 7.9]
1
high 2 no biowaiver
antileprosy &
antituberculosis
medicine
rifampicin (r) +
isoniazid (i)
(r) 300mg +
(i) 150mg
(r) low +
(i) high
(r) high +
(i) borderline
(r) 2 +
(i) 3/1

antituberculosis
medicine
rifampicin (r) +
isoniazid (i) +
pyrazinamide (p)
(r) 150mg +
(i) 150mg + (p)
500mg
(r) low +
(i) high +
(p) high
(r) high +
(i) borderline +
(p) borderline
(r) 2 +
(i) 3/1 +
(p) 3/1

antituberculosis
medicine
rifampicin (r) + isoniazid (i) +
pyrazinamide (p) +
ethambutol (e)
(r) 150mg +
(i) 75mg +
(p) 400mg +
(e) 275mg
(r) low +
(i) high +
(p) high +
(e) high
(r) high +
(i) borderline +
(p) borderline +
(e) low
(r) 2 +
(i) 3/1 +
(p) 3/1
+ (e) 3

antituberculosis
medicine
ritonavir 100mg low low 4 no biowaiver CYP 450 3A4 antiretroviral
unknown whether
poor BA is due to
poor solubility or poor
solubility and
permeability
salbutamol sulfate 4mg high high 1 9.2.1.1
antiasthmatic and
medicine for COPD

25. Working document QAS/04.109/Rev.1
page 25

saquinavir 200mg low low 4 no biowaiver
CYP 450 3A4,
food effect (+) antiretroviral
unknown whether
poor BA is due to
poor solubility or poor
solubility and
permeability

7,5mg (sennoside)


N.R.
N.A.

laxative
local effect
spironolactone 25mg borderline low 4/3 no biowaiver diuretic stavudine 40mg high high 1 9.2.1.1 antiretroviral sulfamethoxazole (s) +
trimethoprim (t)
(s) 400mg +
(t) 80mg
(s) low
(amphiphil) +
(t) low (weak
base)
(s) high +
(t) high
(s) 2 +
(t) 2 no biowaiver G6PD deficiency antibacterial
sulfasalazine 500mg low low 4 N.R.
gastrointestinal, anti-
inflammatory medicine
local effect; unknown
whether poor BA is
due to poor solubility
or poor solubility and
permeability
thiamine hydrochloride 50mg high low 3 9.2.1.2 vitamin triclabendazole 250mg
insufficient
literature low 4/3 no biowaiver
antischistosomal,
antitrematode trimethoprim 200mg
low (weak
base) high 2 no biowaiver antibacterial valproic acid sodium salt 500mg high high 1 9.2.1.1
antiepileptic,
psychotherapeutic
medicine enteric coated tablet

26. Working document QAS/04.109/Rev.1
page 26



verapramil hydrochloride 80mg
low (weak
base) high 2 no biowaiver
antianginal and
antiarrhythmic
medicine



warfarin sodium salt 5mg
low (soluble
1in less than 1
of water)
1
High 1 9.2.1.1
narrow
therapeutic index
medicines affecting
coagulation
zidovudine 300mg high high 1 9.2.1.1 antiretroviral zinc sulfate
10mg (per unit dosage form)
high
low
3
9.2.1.2

diarrhoea in children



1. Pharmaceutical Press Ev. 2004. Clarke's Analysis of Drugs and Poisons. ed.: Pharmaceutical Press, London.
2. Brittain KFsHG. Analytical Profiles of Drug Substances and Excipients . ed.: Oxford University Press.
3. Sweetman S. 2004. Martindale: The Complete Drug Reference. ed.
4. 2004. Dissertation Erika Stippler.
5. 2004. Merck Index. ed.

a WHO Essential Medicines List, 14
th
edition, march 2005 can be found under:

http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf.

b Solubility based on the lowest solubility in the pH range from 1-6.8 at 37°C. "Low" indicates a dose
a
solubility
ratio > 250ml at at least one pH value in this range.
c Permeability based on fraction of the dose absorbed after or al dosing in humans, except where otherwise
indicated. "Low" indicates that less th an 85% of the oral dose were abso rbed commensurate with the highest
oral strength according to the EML
a
.
d The original Biopharmaceutics Classification System (BCS ) can be found under:
http://www.fda.gov/cder/guidance/3618fnl.pdf
Note that the acceptance criteria have been adapted according to
WHO requirements as explained in footnotes 1-3.

27. Working document QAS/04.109/Rev.1
page 27
e See WHO multisource document:
www.who.int/medicines/library/qsm/manual-on-marketing/multisource-contents.html.
f Known potential risks are indicated where appropriate. Where no informatio n is given, this may indicate also
lack of availability of data and should not automatical ly be construed as meanin g that there are no risks
associated with use of the compound. Assessment of risks should be made by the individual country based on
local conditions of use.
N.R. not relevant: locally acting, no significant systemic absorption
N.A. not applicable, locally acting
clavulanic recently classified, references see list of new compounds on the EML (List c)

fixed-dose combination of antituberculosis drugs, will be reviewed by the Expert
Committee

compounds introduced to the EML since March 2005 or no certain classification had
been previously reported

BA bioavailability

Medicine is applied sublingual, major absorption in the oral cavity

28. Working document QAS/04.109/Rev.1
page 28


Ferrous salts
Commonly used iron salts
3
:
- ferrous ascorbate (anhydrous)
- ferrous aspartate (tetrahydrate)
- ferrous chloride (tetrahydrate)
- ferrous fumarate (anhydrous)
- ferrous gluconate (dihydrate)
- ferrous glycine sulphate
- ferrous orotate
- ferrous succinate (anhydrous)
- ferrous sulfate (dried)
- ferrous sulfate (heptahydrate)

Ferrous salts solubility:
- lowest solubility of all commonly used iron salts: ferrous succinate anhydrous,
sparingly soluble in water
5
, D/L 6ml).

Iopanoic acid:
not sufficient solubility at pH 6. 8 expected: 0.015 mg/ml in water.

29. Working document QAS/04.109/Rev.1
page 29
Table B. Substances on the Complementary list of WHO Essential Medicines List (EML)
Drug
a

Highest
oral
strength
according
to WHO
Essential
Medicines
List
a

Solubility
b
Permeability
c

BCS
class
d

Dissoluti
on test
(for
biowaiver
)
e
Potential risks
f
Indication(s)
according to
WHO Essential
Medicines List
(EML)
g

Comments

and
special
dosage form
indications
a

artesunate
50mg
high
borderline (BA
abs
82 +
88%) but dependant on severity of disease
1,2

3/1
9.2.1.2
extent of abs. depends on severity of disease
antimalarial

azathioprine sodium salt 50mg low low 4
no
biowaiver
immunosuppressive,
TDM recommended
immunosuppressi
ve, DMARD
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
calcium folinate
15mg
high
high
1
9.2.1.1

anti-cytotoxic medicine

chlorambucil
2mg
high
insufficient literature (BA
after repeated dosage
>
70% but urinary analytical profile i.v similar to p.o.)
3,4

3/1
9.2.1.2
myolosuppression (leucopenia) = dose limiting toxicity
cytotoxic medicine

cyclosporine
25mg
borderline
low
4/3
no
biowaiver
immunosuppressive, TDM recommended
immunosuppressi ve

clindamycin
150mg
high
high
1
9.2.1.1

antibacterial

cyclophosphamide
25mg
high
high
1
9.2.1.1
myolosuppression (leucopenia) = dose limiting toxicity, accelerated metabolism leading to reduced oral BA after repeated treatment
cytotoxic medicine

30. Working document QAS/04.109/Rev.1
page 30


cycles
cylcoserine
250mg
high
insufficient literature (urinary recovery 65%
5
, 70-90% of the
dose absorbed
6
)
3/1
9.2.1.3
serum levels > 30µg/ml associated with CNS toxicity
antituberculosis medicine

diethylcarbamazine
dihydrogen citrate 100mg high high 1 9.2.1.2
myolosuppression
(leucopenia) = dose
limiting toxicity,
accelerated
metabolism leading to
reduced oral BA after
repeated treatment
cycles antifilarial
doxycycline hydrochloride 100mg high high 1 9.2.1.1 antimalarial ethionamide
250mg
high
insufficient literature (readily abs. from the GI tract
7
)
3/1
9.2.1.3

antituberculosis medicine

ethosuximide 250mg high insufficient literature 3/1 9.2.1.2 antiepileptic etoposide
100mg
low
low
4
no
biowaiver
myolosuppression (leucopenia) = dose limiting toxicity, accelerated metabolism leading to reduced oral BA after repeated treatment cycles
cytotoxic medicine
unknown whether poor BA is due to poor solubility or poor solubility and permeability
flucytosine
250mg
high
borderline (BA
abs
76-
89%)
8,9

3/1
9.2.1.2

antifungal

levamisole
hydrochloride 50mg high
no human data
available 3/1 9.2.1.2
cytotoxic medicine
levofloxacin
500mg
high
high
1
9.2.1.1

antituberculosis medicine

mefloquine hydrochloride
250mg
low
insufficient literature (well absorbed
7
)
4/2
no
biowaiver
pharmacokinetics of mefloquine may be altered by malaria infection
7

antimalarial

31. Working document QAS/04.109/Rev.1
page 31
mercaptopurine
50mg
low
low
4

no
biowaiver

cytotoxic medicine
unknown whether poor BA is due to poor solubility or poor solubility and permeability
methotrexate
sodium salt 2,5mg high low 3 9.2.1.2
severity of adverse
effects depends on
dose and indication
cytotoxic medicine, DMARD
mifepristone - misoprostol
200mg
no literature data available
low
4/3
no
biowaiver

oxytocic

ofloxacin
400mg
high
high
1
9.2.1.1

antituberculosis medicine

oxamniquine
250mg
low
insufficient literature (urinary recovery as single acid 70%
7
)
4/2
no
biowaiver

antischistosomal, antitrematode

p-aminosalicylic acid
500mg
low
borderline (80% urinary recovery
7
)
4/2
no
biowaiver

antituberculosis medicine

penicillamine 250mg high low 3 9.2.1.2 DMARD pentamine
300mg
high
no literature data
3/1
9.2.1.2

anti- pneumocystosis and antitoxoplasmosis medicine

prednisolone 25mg high high 1 9.2.1.1
hormone/
antihormone procarbazine hydrochloride
50mg
high
insufficient literature (urinary recovery 70%, 24h
5
)
3/1
9.2.1.2
myolosuppression (leucopenia) = dose limiting toxicity
cytotoxic medicine

pyridostigmine bromide 60mg high low 3 9.2.1.2 muscle relaxant quinidine sulfate
200mg
high
insufficient literature (BA 70% but first pass
5
)
3/1
9.2.1.2

antiarrhythmic

32. Working document QAS/04.109/Rev.1
page 32

sulfadiazine 500mg borderline low 4/3
no
biowaiver antibacterial sulfadoxine (s) + pyrimethamine (p)
(s) 500mg + (p) 25mg
(s) high + (p) borderline (< 0.1 mg/ml
7
)
(s) insufficient data + (p) low
(s) 3/1+ (p) 4/3
no
biowaiver

antimalarial
combination should be tested according to pyrimethamine requirements
sulfasalazine 500mg low low 4
no
biowaiver DMARD
unknown whether
poor BA is due to
poor solubility or
poor solubility and
permeability
tamoxifen citrate
20mg
high
high
1
9.2.1.1

antihormone



1. Newton P, Suputtamongkol Y, Teja-Isavadharm P, Pukrittayakamee S, Navaratnam V, Bates I, White N 2000. Antimalarial
bioavailability and disposition of artes unate in acute falciparum malaria. Antimicrob Agents Chemother 44(4):972-977.
2. Newton PN, van Vugt M, Teja-Isavadharm P, Siriyanonda D, Rasameesoroj M, Teerapong P, Ruangveerayuth R, Slight T,
Nosten F, Suputtamongkol Y, Looareesuwan S, White NJ 2002. Comparison of oral artesunate and dihydroartemisinin
antimalarial bioavailabilities in acute falciparum malaria. Antimicrob Agents Chemother 46(4):1125-1127.
3. McLean A, Woods RL, Catovsky D, Farmer P 1979. Pharmacokinetics and meta bolism of chlorambucil in patients with
malignant disease. Cancer Treat Rev 6 Suppl:33-42.
4. Silvennoinen R, Malminiemi K, Malminiemi O, Seppala E, Vilpo J 2000. Pharmacokinetics of chlorambucil in patients with
chronic lymphocytic leukaemia: comparis on of different days, cycles and dos es. Pharmacol Toxicol 87(5):223-228.
5. Pharmceutical Press Ev. 2004. Clarke's Analysis of Drugs and Poisons . ed.: Pharmceutical Press, London.
6. Brittain KFsHG. Analytical Profiles of Drug Substances and Excipients . ed.: Oxford University Press.
7. Sweetman S. 2004. Martindale: The Complete Drug Reference. ed.
8. Vermes A, Math t RA, van der Sijs IH, Dankert J, Guch elaar HJ 2000. Population pharm acokinetics of flucytosine:
comparison and validation of three models using STS, NPEM, and NONMEM. Ther Drug Monit 22(6):676-687.
9. Vermes A, Guchelaar HJ, Dankert J 2000. Flucytosine: a review of its pharmacol ogy, clinical indications, pharmacokinetics,
toxicity and drug interactions. J Antimicrob Chemother 46(2):171-179.

33. Working document QAS/04.109/Rev.1
page 33
a WHO Essential Medicines List, 14
th
edition, march 2005 can be found under:
http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf.
b Solubility based on the lowest solubility in th e pH range from 1-6.8 at 37°C. "Low" indicates a
dose
a
solubility ratio > 250ml at at least one pH value in this range.
c Permeability based on fraction of the dose absorbed after oral dosing in humans, except where
otherwise indicated. "Low" indicates that less than 85% of the oral dose were absorbed
commensurate with the highest oral strength according to the EML
a
.
d The original Biopharmaceutics Classification System (BCS ) can be found under:
http://www.fda.gov/cder/guidance/3618fnl.pdf . Note that the acceptance criteria have been
adapted according to WHO requirements as explained in footnotes 1-3.
e See WHO multisource document: www.who.int/medicines/library/qsm/manual-on-
marketing/multisource-contents.html.
f Known potential risks are indicated where appropriate. Where no information is given, this may
indicate also lack of av ailability of data and should not automa tically be construed as meaning that
there are no risks associated with use of the compound. Assessment of risks should be made by the
individual country based on local conditions of use.

N.R. not relevant: locally acting, no significant systemic absorption
N.A. not applicable, locally acting
compounds introduced to the EML since March 2005 or no certain cla ssification had been
previously reported
cytotoxic medicines, possibility of a biowaiver procedure should be reviewed by the
Expert Committee
BA bioavailability

34. Working document QAS/04.109/Rev.1
page 34



Table C. Compounds introduced to the EML since March 2005 or where no certain classification had been previously
reported (these compounds also appear in Table A and Table B)
Drug
a

Highest oral strength according to WHO Essential Medicines List
a

Solubility
b

Permeability
c
BCS class
d
Dissolution test (for biowaiver)
e

Potential risks
f
Indication(s) according to WHO Essential Medicines List (EML)
g

Comments and special dosage form indications
a










amlodipine
5mg
slightly soluble
1
, D/L
5ml
BA
abs
60-65%,
excretion of drug metabolites urine 90-95%
2
1
9.2.1.1

antihypertensive medicine
BA
abs
< 85% ascribed to first
pass metabolism
amodiaquine (base)
200mg
45mg/ml
2
,
D/L 4.4ml
BA > 75%
3

3/1
9.2.1.2
CYP2C8 polymorphism, increased risk for agranulocytosis and hepatotoxicity
4

antimalarial

amoxicillin + clavulanic acid
500mg + 125mg
freely soluble in wate
r
1
, D/L
1.25ml
absorption > 73% (radioactive excretion)
5

1 + 3/1
9.2.1.2

antibacterial
combination should be tested accordi
n
to clavulanic acid requirements
artesunate
50mg
very slightly soluble
6
, D/L
500ml; (weak acid, pk
a
~ 6,4)
BA
abs
82%
1
,
BA
abs
88%
7
,
BA
abs
61%
8

4/2
no biowaiver or 9.2.1.3

antimalarial
permeability depends on severity of disease

35. Working document QAS/04.109/Rev.1
page 35
azithromycin
500mg
practically insoluble in wate
r
1
<
0.01mg/ml, D/L 50000ml
BA
abs
16%
9
;
BA 37%
10,11
;
4/2
no biowaiver

antibacterial
unknown whether poor BA is due to poor solubility or poor solubility and permeability
calcium folinate
15mg
sparingly soluble in water (Ph. Eur. 5.2); very soluble (USP 28); D/L 15ml and 0,015ml, respectively
BA
abs
92%
25mg
12,13
;
BA
abs
73.4%
(15mg)
14
; fully
absorbed; AUC & t
1/2

similar after i.v. & p.o
15

1
9.2.1.1

anti-cytotoxic medicine

levodopa (l) + carbidopa (c)
(l) 250mg + (c) 25mg
(l) high + (c) soluble 1 in 500 of water, freely soluble in 3M HCl
1

(l) high + (c) BA 58%
16
;
BA
abs
88%
(dogs)
17

(l) 1 + (c) 3/1
9.2.1.2
narrow therapeutic index
antiparkinson medicine
combination should be tested according to carbidopa requirements
cefixime
400mg
slightly soluble
2
, D/L
400ml
22-54%
2

4/2
no biowaiver

antibacterial
unknown whether poor BA is due to poor solubility or poor solubility and permeability

36. Working document QAS/04.109/Rev.1
page 36


chlorambucil
2mg
practically insoluble in wate
r
1
, D/L ~
20ml
i.v. vs. p.o similar analytical profile urine = high degree of absorption
18
,
BA
abs
> 70%
after repeated oral dosage
19,20

3/1
9.2.1.3(weak acid, pk
a
~
5,8)
myolosuppression (leucopenia) = dose limiting toxicity; accelerated metabolism leading to reduced oral BA after repeated treatment cycles
21,22

cytotoxic medicine

clindamycin
150mg
500mg/ml
2
,
D/L 0.3ml
,

about 90% of the dose absorbed
1

1
9.2.1.1
diarrhoea/ nausea
antibacterial

cylcoserine
250mg
soluble 100mg/ml
2
,
D/L 2.5ml
65% urinary excreation
2
,
70-90% of a p.o. dose absorbed
23

3/1
9.2.1.2
serum levels > 30µg/ml associated with CNS toxicity
antituberculosis medicine

enalapril
2,5mg
sparingly soluble in wate
r
1
, D/L
0.25ml; dissolves in dilute solutions of alkali hydroxides
1

absorption p.o 69%, urinary recovery 77%, BA 38%, first pass 10%
24
;
p.o. children, urinary recovery ~ absorption 50%
25

3
9.2.1.3

antihypertensive medicine

37. Working document QAS/04.109/Rev.1
page 37
ethionamide
250mg
slightly soluble in water at 25°C
2
,
D/L < 250ml
readily absorbed from the gastrointestinal tract, extensively metabolised, probably in the liver, less than 1% of a dose appears in the urine as unchanged drug
1

3/1
9.2.1.2

antituberculosis medicine

etoposide
100mg
practically insoluble in wate
r
2
, D/L
1000ml
excretion 30- 50% unchanged in the urine, 20% as metabolites = 50-70%
2
,
absorption 48,4% and 57%
23
, 60,6%
absorption in children
26

4/2
no biowaiver
myolosuppression (leucopenia) = dose limiting toxicity; great variability in absorption (all references)
cytotoxic medicine
unknown whether poor BA is due to poor solubility or poor solubility and permeability
ferrous salt
equivalent to 60mg iron
high (see footnote)
low
3
9.2.1.2

antianaemia medicine
commently used salts: see footnote
ferrous salt (fs) + folic acid (fa)
equivalent to 60mg iron + 400µg folic acid
(fs) high (see footnote) + very slightly soluble in wate
r
2
, D/L
2,5ml; 0,0016mg/ml
(fs) low + (fa) low (urinary recovery 28,5%
23
)
(fs) 3 + (fa) 3/1
9.2.1.2

antianaemia medicine (during pregnancy)
combination should be tested according to requirements for BCS class 3 compounds; commonly used iron salts: see footnot
e

38. Working document QAS/04.109/Rev.1
page 38


(25°C) wate
r
23
, D/L
250ml
flucytosine
250mg
soluble 15mg/ml
2
,
D/L 17ml; 14,2mg/ml
23
;
D/L 17,6ml
BA
abs
76-
89%
27,28

1(borderline)
9.2.1.1

antifungal

levofloxacin
500mg
high (30-300 mg/ml)
29

D/L: 16.7 ml
high (oral vs. iv 100% BA; CaCo2 permeability high)
29

1
9.2.1.1
for main side effects refer to
30

antituberculosis medicine

mebendazole
500mg
practically insoluble in water (both monohydrate and anhydrous
1
,
also both permitted in Pharm. Int.), D/L > 50000ml
BA
abs
2%
31
;
urinary recovery 2% of a orally administered dose
32

4/2
N.A.

anthelminic
anthelmintics usually applied orally for action in GI tract: solubility more important than permeability
medroxyprogesterone acetate
5mg
practically insoluble in wate
r
2
, 1 g in
>10 000 ml, < 0.1 mg/ml, D/L >50 ml
in rats + dogs BA 27% first pass metabolism, self induced metabolism; 16% and very variable
2

3/1
9.2.1.2

progestogen
extent of first pass metabolism in humans uncertain

39. Working document QAS/04.109/Rev.1
page 39
mercaptopurine
50mg
low (insoluble in water pka 7.7/ 11.0, < 0.1 mg/ml)
2
,
D/L >500 ml
2
BA
oral
von aza
47%, first pass, 50% in urine
2

4/2
no biowaiver
antimetabolite, TDM suggested by Lennard (1)
cytotoxic medicine
unknown whether poor BA is due to poor solubility or poor solubility and permeability
mifepristone - misoprostol
200mg
no information available
BA 70%; also reported 40% after 100 mg oral dose
2

4/3
no biowaiver

oxytocic
insufficient information available
niclosamide
500mg
5-8mg/l (20°C)
33
, D/L
77000ml
2-25% of a dose of 2g radiolabeled drug recovered in the urine, rest faeces
33

4
N.A.
local use
anthelminic
anthelmintics usually applied orally for action in GI tract: solubility more important than permeability
ofloxacin
400mg
high (30-300 mg/ml)
29
,
D/L 13 ml
dose prop. 100% BA
29

1
9.2.1.1
for main side effects refer to
30

antituberculosis medicine

oxamniquine
250mg
low (1 in 3300 at 27°C, 0.3 mg/ml)
23
,
D/L 825 ml, weak acid (?) pk
a
not
located
readily absorbed, urinary excretion 70% as single acid
1
4/3
no biowaiver
no significant toxic effects on liver, kidney or heart, dose 15 mg/kg
1

antischistosomal, antitrematode

p-aminosalicylic acid
500mg
low (1 g in 600 ml, 1.66 mg/ml)
23
;
D/L 301 ml, weak acid, pka not located
borderline, 80% excretion in urine
1

4/2
no biowaiver

antituberculosis medicine
borderline in both solubility and permeability

40. Working document QAS/04.109/Rev.1
page 40


pentamine
300mg
high (1 in 10 -> 100 mg/ml)
2
, D/L
3 ml
No information available
3/1
9.2.1.2

anti- pneumocystosis and antitoxoplasmosis medicine

potassium iodine
60mg
very soluble in water, D/L > 0.06ml, 133mg/ml
34
,
D/L 0.45ml
BA 96.4%
35
;
urinary recovery 89%, faeces 11%
36

1
9.2.1.1

thyroid hormones and antithyroid medicines

procarbazine hydrochloride
50mg
high (200 mg/ml)
23
,
D/L 0.25 ml
readily absorbed, 70% dose -> urine after 24h
2

3/1
9.2.1.2
tumour inhibitor, hematologic
2

cytotoxic medicine

pyrantel embonate
250mg
low (practically insoluble in water, 1 g in >10 000 ml
2
,
< 0.1 mg/ml), D/L >2500 ml
16 % BA
oral

(palmoate), 41% oral BA (citrate)
37

4
N.A.
local use
anthelminic
chewable tablet; anthelmintics usually applied orally for action in GI tract: solubility more important than permeability
quinidine sulfate
200mg
high (10 mg/ml)
23
,
D/L 20 ml
rapidly abs. BA 70%; varies widely, first pass
2

3/1
9.2.1.2
narrow therapeutic index
antiarrhythmic

ranitidine hydrochloride
150mg
high (freely soluble in wate
r
2
>
1000 mg/ml), D/L 0.15
50% BA, first pass
2,38

3/1
9.2.1.2

antiulcer medicine

41. Working document QAS/04.109/Rev.1
page 41
sulfadoxine
25mg
very slightly soluble in wate
r
2
, D/L <
250ml
readily absorbed after oral administration
2
3/1
9.2.1.2

antimalarial

tamoxifen citrate
20mg
high (very slightly soluble in wate
r
1
, 0.1
mg/ml -1 mg/ml), D/L 200 ml
BA
abs
~
100%
39

1
9.2.1.1
endometrical cancer, uterine sarcoma
1

antihormone

zinc sulfate
10mg (per unit dosage form)
high (very sol in water)
1
, D/L
0.01, same solubility for all hydrates of the sulfate
11 % absorbed, with meal versus iv., abs. 20- 30%
3
9.2.1.2

diarrhoea in children


1. Sweetman S. 2004. Martindale: The Complete Drug Reference. ed.
2. Pharmceutical Press Ev. 2004. Clarke's Analysis of Drugs and Poisons . ed.: Pharmceutical Press, London.
3. Krishna S, White NJ 1996. Pharmacokinetics of quinine, chloroquine and amodi aquine. Clinical implications. Clin
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40. 2004. Merck Index. ed.

a WHO Essential Medicines List, 14
th
edition, march 2005 can be found under:
http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf

b Solubility based on the lowest solubility in the pH range from 1-6.8 at 37°C. "Low" indicates a dose
a
solubility ratio > 250ml at at least one pH value in
this range.
c Permeability based on fraction of the dose absorbed after oral dosing in humans, except wher e otherwise indicated. "Low" indicates that less than 85%
of the oral dose were absorbed commensurate with the highest oral strength according to the EML
a
.

44. Working document QAS/04.109/Rev.1
page 44

d The original Biopharmaceutics Classification System (BCS ) can be found under:
http://www.fda.gov/cder/guidance/3618fnl.pdf
Note that the acceptance
criteria have been adapted according to WHO re quirements as explained in footnotes 1-3.
e See WHO multisource document:
www.who.int/medicines/library/qsm/manual-on-marketing/multisource-contents.html
f Known potential risks are indicated where appropriate. Where no information is given, this may indicate also lack of availab ility of data and should not
automatically be construed as meaning that there are no risks associated with use of the compound. Assessment of risks should b e made by the
individual country based on local conditions of use.
N.R. not relevant: locally acting, no significant systemic absorption
N.A. not applicable, locally acting
clavulanic newly classified, references see list of new compounds on the EML
fixed dose combination of antituberculosis drugs, will be reviewed by the Expert Committee
cytotoxic medicines, possibility of a biowaiver procedure should be reviewed by the Expert Committee
BA bioavailability Ferrous salts
Commonly used iron salts
1
:
- ferrous ascorbate (anhydrous)
- ferrous aspartate (tetrahydrate)
- ferrous chloride (tetrahydrate)
- ferrous fumarate (anhydrous)
- ferrous gluconate (dihydrate)
- ferrous glycine sulphate
- ferrous orotate

45. Working document QAS/04.109/Rev.1
page 45
- ferrous succinate (anhydrous)
- ferrous sulfate (dried)
- ferrous sulfate (heptahydrate)

Ferrous salts solubility:
- lowest solubility of all commonly used iron salts: ferrous succinate anhydrous,
sparingly soluble in water
40
, D/L 6ml)

***